Study Shows Fatigue Persists in Some Cases Even When Rheumatoid Arthritis Is Controlled

The fatigue that often accompanies rheumatoid arthritis (RA) can be as distressing and disabling as the pain – and often harder to treat. RA-related fatigue has been associated with molecules called cytokines that promote inflammation, such as tumor necrosis factor (TNF), and the use of biologics that block TNF have been shown to somewhat reduce fatigue. But a new study published online in the journal Rheumatology quantifies just how stubborn RA-related fatigue is – even when the disease itself is well controlled with an anti-TNF medication – and characterizes which patients are most likely to beat it.
Researchers at the University of Aberdeen, in Scotland, looked at data on more than 13,000 RA patients (recruited between October 2000 and November 2008) who were about to start an anti-TNF biologic. The data were from the British Society for Rheumatology Biologics Register for RA.

They identified 2,652 people with severe fatigue* at baseline. Severe fatigue takes into account numerous quality of life measures, says Neil Basu, MD, PhD, the lead author of the study.

Six months after starting an anti-TNF, 271 (10.2 percent) of the patients met the criteria for disease remission** based on a disease activity score (DAS28) that includes measures of tender and swollen joints and inflammation in the blood, among other factors.

The researchers found that disease remission didn’t equate with full fatigue remission in most cases. Only 37.3 percent – 101 out of 271 patients – reported full remission of their fatigue, an additional 124 reported partial remission and 46 of the patients experienced no meaningful improvement in fatigue despite being in full disease remission.

Fatigue From Other Factors?

So who still had residual fatigue? Those who did not achieve full fatigue remission were more likely to have had histories of depression, stroke and/or hypertension, and they were more likely than those who did experience fatigue remission to have used antidepressants and corticosteroids at baseline, Dr. Basu and his colleagues reported. They also had worse baseline scores on all patient-reported variables.

Although the study does not explain why people whose RA is in remission continue to experience fatigue, it raises several possibilities, says Arthur Kavanaugh, MD, a professor of medicine at the University of California, San Diego, who was not involved with the study. “One is that our definitions of remission are not stringent enough, and that subclinical inflammation may be causing fatigue. The other is that all fatigue in patients with rheumatic disease does not relate to inflammation, or even perhaps to their disease,” he says. “Both of these may be true, to different extents, for individual patients.”

Other potential causes of fatigue in people with RA may include sleep disorders, pain, depression, medications and physical inactivity, says Dr. Basu. “More research is required to understand the involved biological pathways.”

One weakness of the study is that the data do not reveal why patients had received prescriptions for antidepressants and corticosteroids. “These may be prescribed for patients with secondary fibromyalgia or chronic fatigue symptoms,” says Susan Goodman, MD, a rheumatologist at the Hospital for Special Surgery in New York, who also was not involved in the study. “This doesn’t weaken the strength of the observation that fatigue in early RA may be due to active disease and frequently responds to anti-TNF therapy, while fatigue described in those who have achieved DAS remission remains more challenging to explain and to treat.”

Beyond Medications

“Patients describe fatigue as being harder to deal with than pain, and frequently more limiting, so I do think it is a serious limitation on the health-related quality of life for patients living with RA,” says Dr. Goodman. For people whose fatigue doesn’t respond to TNF therapy, other causes should be examined, she says. “Pain and depression are high on the list of possibilities. There are other common causes of fatigue, but the most common is typically caused by poor sleep patterns. I discuss sleep hygiene – do they go to sleep at different times every day, have late dinners, or watch scary TV shows in bed? If sleep hygiene isn’t contributing to poor sleep, I determine if other medical conditions such as reflux or sleep apnea may be disturbing sleep.”

Determining the cause will also help determine the solution. “The characteristics of these patients do suggest that adjunctive non-pharmacological interventions should be tested,” says Dr. Basu, noting that increasing levels of physical activity and talk therapies may help, too.

Author: Mary Anne Dunkin for the Arthritis Foundation

*Severe fatigue was defined as scoring, on a scale called the SF-36, at or below the 5th percentile compared to sex- and age-matched people in the general population. “The SF-36 incorporates multiple quality of life domains, including a measure of fatigue – aka the vitality score,” says Dr. Basu.

**Disease remission was defined as scoring lower than 2.6 on the DAS28. A standard method to evaluate disease activity in RA, the DAS28 combines the number of tender and swollen joints, the level of inflammation in the blood and how the patient rates their current disease ­to produce an overall score.